Formulation and Use and Manufacture Thereof

ABSTRACT

This invention relates to a liquid pharmaceutical formulation for delivering nicotine to a subject. This invention also relates to a method and a system for delivering nicotine as well as manufacturing and use of said liquid pharmaceutical formulation.

CROSS REFERENCE TO RELATED PATENT APPLICATIONS

The present application is a divisional of U.S. patent application Ser.No. 10/345,676 filed Jan. 16, 2003 which claims benefit of U.S. PatentApplication Ser. No. 60/351,178, filed Jan. 21, 2002, each of which isexplicitly incorporated herein by reference in its entirety and for allpurposes.

FIELD OF THE INVENTION

This invention relates to a liquid pharmaceutical formulation fordelivering nicotine to a subject. This invention also relates to amethod and a system for delivering nicotine as well as manufacturing anduse of said liquid pharmaceutical formulation.

BACKGROUND OF THE INVENTION

Tobacco Dependence and Reduction Thereof

In recent years, with the recognition of the harmful effects of tobaccosmoking, there have been numerous campaigns and programs by governmentalagencies and various health groups and other interested organisations todisseminate information about the adverse health effects resulting fromtobacco smoking. Moreover, and as a result of this recognition of theharmful effects, there have been many programs directed to attempts inreducing smoking incidence.

Nicotine is an organic compound and is the principal alkaloid oftobacco. Nicotine is the chief active ingredient in the tobacco used incigarettes, cigars, snuff and the like. Nicotine is also an addictivedrug, though, and smokers characteristically display a strong tendencyto relapse after having successfully stopped smoking for a time.Nicotine is the world's second most used drug, after caffeine fromcoffee and tea.

The main problem with tobacco smoking is its enormous implications onhealth. Today it is estimated that smoking-related diseases cause some3-4 million deaths per year. In the US Surgeon General's 1988 report onThe Health Consequences of Smoking, it was estimated that in the USalone about 300.000 deaths are caused each year by diseases related tocigarette smoking. In fact, excessive smoking is now recognized as oneof the major health problems throughout the world. This grim consequenceof tobacco smoking has urged many medical associations and healthauthorities to take very strong actions against the use of tobacco.

Even though tobacco smoking is decreasing in many developed countriestoday it is hard to see how the societies could get rid of the world'ssecond most used drug.

The most advantageous thing a heavy smoker can do is to reduce orpreferably even stop smoking completely. Experience shows, however, thatmost smokers find this extremely difficult since, mostly, tobaccosmoking result in a dependence disorder or craving. The WHO has in itsInternational Classification of Disorders a diagnosis called TobaccoDependence. Others, like the American Psychiatric Association call theaddiction Nicotine Dependence. It is generally accepted that thesedifficulties to stop smoking result from the fact that those heavysmokers are dependent on nicotine. The most important risk factors are,however, substances that are formed during the combustion of tobacco,such as carcinogenic tar products, carbon monoxide, aldehydes, andhydrocyanic acid.

Effects of Nicotine

The administration of nicotine can give satisfaction and the usualmethod is by smoking, either by smoking e.g., a cigarette, a cigar or apipe, or by snuffing or chewing tobacco. However, smoking has healthhazards and it is therefore desirable to formulate an alternative mannerof administering nicotine in a pleasurable manner that can be used tofacilitate withdrawal from smoking and/or used as a replacement forsmoking.

Upon smoking of a cigarette, nicotine is quickly absorbed into thesmoker's blood and reaches the brain within around ten seconds afterinhalation. The quick uptake of nicotine gives the consumer a rapidsatisfaction, or kick. The satisfaction, then, lasts during the time ofsmoking the cigarette and for a period of time thereafter. Thepoisonous, toxic, carcinogenic, and addictive nature of smoking hasprovided efforts for methods, compositions and devices, which help inbreaking the habit of smoking.

Nicotine is an addictive poisonous alkaloid C5H4NC4H7NCH3, derived fromthe tobacco plant. Nicotine is also used as an insecticide.Approximately forty milligrams of nicotine may kill an adult (MerckIndex).

Nicotine Replacement Products

One way to reduce smoking is to provide nicotine in a form or mannerother than by smoking and some products have been developed to fulfillthis need. Nicotine containing formulations are currently the dominatingtreatments for tobacco dependence.

The success in achieving reduction in the incidence of smoking has beenrelatively poor using presently known products. State of the artinvolves both behavioral approaches and pharmacological approaches. Morethan 80% of the tobacco smokers who initially quit smoking after usingsome behavioral or pharmacological approach to singly reduce smokingincidence generally relapse and return to the habit of smoking at theirformer rate of smoking within about a one year's period of time.

As an aid for those who are willing to stop smoking there are severalways and forms of nicotine replacement products available on the market,such as nicotine chewing gums according to U.S. patent application No.3,845,217. Several methods and means have been described for diminishingthe desire of a subject to use tobacco, which comprises the step ofadministering to the subject nicotine or a derivative thereof asdescribed in e.g., U.S. patent application No. 5,939,100 (nicotinecontaining microspheres) and U.S. patent application No. 4,967,773(nicotine containing lozenge).

The effects of pH on the absorption of nicotine is discussed e.g., inEur J Clin Pharmacol, Vol. 56, 2001, pages 813-818, L. Molander et al,“Pharmacokinetic investigation of a nicotine sublingual tablet”. Theeffects of pH on a liquid nicotine formulation for administration to theoral cavity are though not disclosed.

The use of skin patches for transdermal administration of nicotine hasbeen reported (Rose, in Pharmacological Treatment of Tobacco Dependence,(1986) pp. 158-166, Harvard Univ. Press). Nicotine-containing skinpatches that are in wide use today can cause local irritation and theabsorption of nicotine is slow and affected by cutaneous blood flow.

Nicotine-containing nose drops have been reported (Russell et al,British Medical Journal, Vol. 286, p. 683 (1983); Jarvis et al., BritishJournal of Addiction, Vol. 82, p. 983 (1987)). Nose drops, however, aredifficult to administer and are not convenient for use at work or inother public situations. Ways of administrating nicotine by way ofdelivery directly into the nasal cavity by spraying is known from U.S.patent application No. 4,579,858, German Application No. DE 32 41 437and International Publication No. WO/93 127 64. There may, though, belocal nasal irritation with use of nasal nicotine formulations. Thedifficulty in administration also results in unpredictability of thedose of nicotine administered.

Also, inhaling devices resembling a cigarette are known for uptake ofnicotine vapors as suggested in U.S. patent application No. 5,167,242.An aerosol for deposing nicotine in the lungs is disclosed in GermanApplication No. DE 32 41 437.

Mouth sprays comprising nicotine are known in the art, e.g., accordingto U.S. patent application No. 6,024,097 wherein is disclosed a methodof assisting a smoker in giving up the smoking habit whereby is used aplurality of aerosol dispensers comprising progressively lesserconcentrations of nicotine. The aerosol is intended to be administeredinto the mouth. The liquid in the dispensers essentially consists ofnicotine and alcohol.

A similar mouth spray is disclosed in U.S. patent application No.5,810,018, whereby in addition the aerosol comprises progressivelygreater concentrations of at least one selected stimulant.

International Publication No. WO 98/24420 discloses an aerosol devicewith an active and a propellant. The device may be used for e.g.,sublingual administration. Nicotine is mentioned as an active in a long“laundry list” of drugs. There are though no examples on nicotineformulations.

U.S. patent application No. 5,721,257 discloses a method for treating acondition responsive to nicotine therapy comprising a first treatmentwith transdermally administered nicotine and a second treatment withtransmucosally administered nicotine. It is stated that thetransmucousal administration may be accomplished via an aerosol to thenasal membranes. No administration to the oral cavity is disclosed.

International Publication No. WO 97/38663 discloses a buccal aerosolspray using a non-polar solvent. Nicotine is mentioned as one usefulactive in this spray.

U.S. patent application No. 5,955,098 likewise discloses a buccalnon-polar spray wherein nicotine may be an active.

None of the known mouth sprays comprise any buffering and/or pHregulating means.

Prior Art and Problems Thereof

The captioned means and methods do not satisfy the craving that certainusers of tobacco experience. Specifically these means and methodsgenerally do not provide for a sufficiently rapid uptake of nicotinewithout adverse effects.

This means that none of the hitherto known means and methodssatisfactorily fulfills the following well-known NRT teaching by Russelet al:

I: A fast delivery or “boost” of nicotine, sufficiently rapid to givepositive subjective nicotine effects in contrast with current nicotinegums and patches, will lead to faster craving relief, and

II: faster craving relief will give better craving control, and

III: better craving control should result in higher overall quit rates.

For the captioned see Russel, M. A. H., Stapleton, J. A. and FeyerabendC. Nicotine boost per cigarette as the controlling factor of intakeregulation of smokers; In: Clark et al. (Eds.) Effects of Nicotine onBiological Systems II, Advances in Pharmacological Sciences, BirkhauserVerlag, Basel, (1995) 233-238.

In light of the aforementioned problems there is a strong need andinterest to develop means and methods for the administration of nicotineto provide a fast satisfaction to a person craving for nicotine or toprovide a sense of smoking satisfaction without smoking, whereby alsomay be avoided problems associated with the prior art means and methods.The present invention addresses said need and interest.

SUMMARY OF THE INVENTION

In view of the foregoing disadvantages known in the art when trying todeliver nicotine to a subject so as to obtain a rapid transmucosaluptake of nicotine in the oral cavity of the subject the presentinvention provides a new and improved product, systems and methods forobtaining a rapid transmucosal uptake of nicotine in the oral cavity ofthe subject.

Objects of the present invention are to provide an efficient andeffective product, as well as methods and systems for a rapid uptake ofnicotine in a subject to avoid the disadvantages of previously knownproducts and methods. The present invention also satisfactorilysatisfies the above teaching of Russel et al.

Thus, the present invention provides a method for delivering nicotine inany form to a subject comprising administering to a subject a liquidpharmaceutical formulation containing nicotine in any form into the oralcavity of the subject and allowing the nicotine in any form to beabsorbed into the systemic circulation of the subject essentially byrapid buccal uptake of nicotine as well as a method for manufacturingsaid liquid pharmaceutical formulation.

The present invention also provides a method for obtaining reduction ofthe urge to smoke or use tobacco containing material and/or forproviding a fast sense of smoking satisfaction without smoking,comprising the steps of replacing at least partly the tobacco containingmaterial with said liquid pharmaceutical formulation, administering to asubject a liquid pharmaceutical formulation containing nicotine in anyform into the oral cavity of the subject and allowing the nicotine to besystemically absorbed by the subject essentially by buccal uptake ofnicotine.

Furthermore, the present invention provides a system for deliveringnicotine in any form to a subject, comprising said liquid pharmaceuticalformulation and at least one other means for obtaining reduction of theurge to smoke or use of tobacco as well as a system for obtainingreduction of the urge to smoke or otherwise use of tobacco and/or forproviding a sense of smoking satisfaction without smoking, comprising aliquid pharmaceutical formulation as per above and at least one othermethod for obtaining reduction of the urge to smoke or otherwise usetobacco. Said system may be a system wherein the at least one othermethod is selected from the group consisting of administration throughchewing gums, nasal sprays, transdermal patches, inhaling devices,lozenges, tablets and parenteral methods, subcutaneous methods,intravenous methods, rectal methods, vaginal methods and transmucousalmethods; or other use of tobacco.

The present invention provides for a flexible, convenient and discreteuse in comparison with other means for transmucosal delivery ofnicotine, e.g., chewing gums, lozenges and tablets. No chewing orsucking is necessary. Further and in contrast to other transmucosaldosage forms the present liquid pharmaceutical formulation providesnicotine in a form being directly buccally absorbable by a subject.Known formulations for nasal delivery of nicotine are inconvenient—sideeffects include running nose, nasal irritation and irritation of theeyes. The nicotine in chewing gums, lozenges and tablets need pass atransformation phase, involving e.g., mastication, disintegration,melting and/or dissolution, prior to being present in a directlyabsorbable form. A nicotine patch provides for a discreteadministration, but does not provide for a fast uptake of nicotine.

A product according to the present invention is alkalized by bufferingand/or pH regulation in such a way that upon administration of theliquid pharmaceutical formulation the pH of the liquid of the oralcavity is increased by 0.3-4 pH units, or preferably increased by0.5-2.5 pH units.

Use of said product will according to the invention rapidly delivernicotine in any form to a subject and will also provide for obtaining aquick and/or sustained and/or complete reduction of the urge to smoke oruse tobacco and/or for providing a sense of smoking satisfaction withoutsmoking resembling the sense of smoking satisfaction obtained afterregular smoking or use of tobacco.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagram showing venous blood plasma level concentrations ofnicotine after two different ways of administering nicotine. For bothways of administration one unit dose was administered at time zero. Nofurther doses were administered. 50 persons, all being nicotine users,took part in this test. “Spray” represents 200 μl of a liquidpharmaceutical formulation according to below Example 4 being sprayedunder the tongue. This unit dose comprised 3.5 mg nicotine measured asfree base. “Microtab” represents one tablet of Nicorette® Microtab,comprising 4 mg nicotine measured as free base. Nicorette® Microtab ispharmacologically equivalent to Nicorette® Gum. “Spray” comprises abuffer. “Microtab” comprises no buffer. With “Spray” the liquidpharmaceutical formulation was held in the mouth for one minute beforeswallowing. With “Microtab” the tablet was kept under the tongue untildissolved. Each symbol on the respective graph represents onemeasurement of nicotine in venous blood plasma.

FIG. 2 shows mean plasma concentrations after sublingual administrationof three liquid pharmaceutical formulations with pH 6, 7 and 8.5respectively. For each formulation 200 μl was sprayed under the tongueat time zero. For all said three formulations the concentration ofnicotine was 10 mg/ml, i.e., each 200 μl spray dose as above contained 2mg nicotine calculated as free base. The formulation with pH 8.5 was aformulation according to below Example 1. The formulations with pH 7 andpH 6 were formulations according to below Example 2 and Example 3respectively.

FIG. 3 compares the venous blood nicotine plasma profile vs. time of asingle dose of the current Nicorette® Gum, extra strength (4 mg), withthe corresponding plasma profile when smoking a “light” (low-nicotine)cigarette. One objective with the present invention is to obtain abuccal nicotine formulation providing for a pK profile being closer tothe pK profile for a cigarette than is provided using presently knownbuccal nicotine formulations.

FIG. 4 shows the mean score values from 52 smoking volunteers in arandomized open study of the “urge to smoke” (craving), as estimated andrecorded on a visual analogue scale (VAS) as a function of time when thesame formulations as in FIG. 1 were used. The craving scores wererecorded directly after smoking one cigarette and during the abstinenceof 7 hours before the administration of the nicotine products. Thescores were then recorded more frequently during 1 hour after theadministration. The heart rate was also monitored in this study. Thisfigure clearly shows that the present invention provides for a muchfaster reduction of the urge to smoke score than do present buccalnicotine formulations. For example, about 2 minutes after administrationof a formulation according to the present invention the craving score isreduced by 50%. With Nicorette® Microtab a 50% decrease in craving scoreis obtained only more than 10 minutes after administration.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Definitions

The terms “tobacco”, “tobacco containing material” and similar areherein intended to mean such material for any type of use of tobaccoincluding smoking, snuffing or chewing whereby is used inter alia acigarette, a cigar, pipe tobacco, snuff and chewing tobacco.

The term “fast reduction of the urge to smoke or use tobacco” is hereinintended to mean an initial priming of the subject so as to achieve areduction of the urge to smoke or use tobacco.

The term “transient” is intended to pertain to a non-permanent change ofa biological and/or physiological state, upon which after a certainperiod of time said state will return to its value or behavior prior tosaid change.

The term “buccal” and “buccally” are herein intended to pertain to allof or any part of the soft tissue lining of the oral cavity.

The term “liquid of the oral cavity” is herein intended to mean salivaand/or saliva mixed with a quantity of the liquid pharmaceuticalformulation.

The term “incidence of administration” is herein intended to meanadministration of one or more single doses of the liquid pharmaceuticalformulation within the same time frame, said time frame being dependenton the needs of the subject receiving the administration, said timeframe extending from a few seconds to around ten minutes.

The Buffering Agent and the pH Regulating Means

Absorption of nicotine from the oral cavity to the systemic circulationis dependent on the pH of the saliva and the pKa of nicotine, which isabout 7.8. Assuming a pH of the saliva of 6.8 only about 10% of thenicotine in saliva will be in the free base form. Thus, in order topromote absorption of nicotine in a free base form, which is the formpredominantly absorbed through the mucosa, the pH of the saliva must beincreased. At a pH of 8.8 about 90% of the nicotine in saliva will thenbe in the free base form.

Hence and according to the invention, the liquid pharmaceuticalformulation is alkalized by buffering and/or pH regulation. This may beachieved by including physiologically acceptable buffering substances oragents, or by other means. With other means it is intended to includebuffering by any component in the product, which may not normally act asa buffering agent, such as a self-buffering additive and/or pHregulating forms of nicotine.

By buffering and/or pH regulation thereby increasing the pH of thesaliva the uptake of nicotine is changed, e.g., increased compared tothe nicotine uptake when the saliva is not alkalized by buffering and/orpH regulation. Also, since the transmucosal uptake of nicotine in theoral cavity according to the invention is faster than for nicotine notbeing buffered and/or pH regulated according to the invention, lessnicotine will be swallowed and reach the gastrointestinal (GI) tract.The nicotine that reaches the GI tract will be subjected to first passmetabolism, which reduces the total amount of intact nicotine absorbedadditionally reducing the rate of nicotine absorption. This means thatthe absorption kinetics of nicotine that is not co-administered with abuffer according to the invention will generally be slower and thebioavailability will generally be lower than when administered togetherwith a buffer.

For buffering may be used one or more buffering agents selected from thegroup consisting of carbonates including bicarbonate or sesquicarbonate,glycinate, phosphate, glycerophosphate or citrate of an alkali metal,such as potassium or sodium, or ammonium, and mixtures thereof.

Further embodiments may use trisodium or tripotassium citrate, andmixtures thereof.

Still further embodiments may comprise different phosphate systems, suchas trisodium phosphate, disodium hydrogen phosphate; and tripotassiumphosphate, dipotassium hydrogen phosphate, and calcium hydroxide, sodiumglycinate; and mixtures thereof.

Alkali metal carbonates, glycinates and phosphates are preferredbuffering agents.

The pH regulation may also be obtained by using pH-regulating forms ofnicotine, e.g., nicotine free base.

The amount of the buffering agent or agents in the liquid pharmaceuticalformulation is preferably sufficient in the specific embodiments toraise the pH of the saliva to above 7, as specified above and, tomaintain the pH of the saliva in the oral cavity above 7, e.g., pH 7-11.Otherwise expressed the liquid pharmaceutical formulation should bealkalized by buffering and/or pH regulation in such a way that uponadministration to a subject the pH of the liquid of the oral cavity ofthe subject is transiently increased by about 0.3-4 pH units, preferablyby about 0.5-2.5 pH units. The amount of buffering agent(s) required toachieve such an increase in pH is readily calculated by a person skilledin the art.

The Active Ingredient

The active ingredient in the present invention is nicotine. When usedherein without further description “nicotine” refers to3-(1-methyl-2-pyrrolidinyl)-pyridine, in any form, including syntheticnicotine as well as nicotine extracts from tobacco plants, or partsthereof, such as the genus Nicotiana alone or in combination. Thenicotine may be formulated in different forms, e.g., in differentcomplexes or salts or as free base.

According to the invention, the liquid pharmaceutical formulationproduct comprises nicotine in any form to provide a fast transmucosaluptake of the nicotine in the oral cavity of a subject so as to obtain areduction of the urge to smoke and/or use tobacco, and/or a rapid“nicotine kick” and/or a “nicotine head rush”. Thereby may also beachieved a systemic maintenance level of nicotine.

The nicotine should be in a saliva soluble form to facilitate thesubsequent uptake of the nicotine from the saliva in the oral cavityinto the systemic circulation of the subject.

In preferred embodiments, the nicotine in any form is primarily selectedfrom the group consisting of the free base form of nicotine, a nicotinesalt, a nicotine derivative, a nicotine inclusion complex or nicotine inany non-covalent binding; and mixtures thereof.

Still further the inclusion complex may be a cyclodextrin, such ascyclodextrin.

Even more further the nicotine salt may be a tartrate, hydrogentartrate, citrate or malate.

According to the invention, the uptake of the nicotine through anytissue or mucosa in the oral cavity is improved in relation to theuptake obtained by a liquid nicotine-containing pharmaceuticalformulation devoid of alkalizing buffering agents or devoid ofalkalizing pH-regulating means.

The nicotine may act as a stimulant to e.g., obtain a rapid reduction ofthe urge to smoke or to use tobacco.

The most preferable embodiment incorporates nicotine as the free baseform or as a water-soluble pharmaceutically acceptable salt, or as aninclusion complex, such as a cyclodextrin complex, e.g., β-cyclodextrin.But any other suitable pharmaceutically acceptable form may also beemployed.

Numerous nicotine salts are known, and may be used, e.g., the saltspresented in Table 1, such as preferably the tartrate, hydrogentartrate, citrate, malate, and/or hydrochloride. TABLE 1 Possible acidsused for nicotine salt formation Molar ratio* of Acid Acid:nicotineFormic 2:1 Acetic 3:1 Propionic 3:1 Butyric 3:1 2-Methylbutyric 3:13-Methylbutyric 3:1 Valeric 3:1 Lauric 3:1 Palmitic 3:1 Tartaric 2:1Citric 2:1 Malic 2:1 Oxalic 2:1 Benzoic 1:1 Gentisic 1:1 Gallic 1:1Phenylacetic 3:1 Salicylic 1:1 Phthalic 1:1 Picric 2:1 Sulfosalicylic1:1 Tannic 1:5 Pectic 1:3 Alginic 1:2 Hydrochloric 2:1 Chloroplatinic1:1 Silicotungstic 1:1 Pyruvic 2:1 Glutamic 1:1 Aspartic 1:1*recommended upon manufacturingAmount of the Nicotine in the Liquid Pharmaceutical Formulation

The nicotine in any form is according to the invention formulated toprovide the subject with a dose to achieve an effect. The effect may beto provide a sense of smoking satisfaction without smoking. Anothereffect of the administered nicotine in any form may be a reduction ofthe urge to smoke or use tobacco.

The effect may also be a combination of a reduction of said urge andproviding a sense of smoking satisfaction without smoking. The amount ofthe nicotine should be sufficient to provide such an effect in asubject. This amount may, of course, vary from person to person.

According to the invention, embodiments of the liquid pharmaceuticalformulation comprise nicotine in such concentrations that the amount ofnicotine delivered at each incidence of administration is about 0.05-10mg calculated as the free base form of nicotine, preferably about 0.25-6mg and most preferably about 0.5-4 mg.

Release and Uptake of Nicotine

Presently existing pharmaceutical administration forms for oraladministration of nicotine normally provide a slow release and a slowuptake of the nicotine compared to smoking. The slow uptake of thenicotine provides a t_(max), i.e., the time-point where the nicotine hasits maximum level measured in the plasma of venous blood after a singledose at about 30-45 minutes after administration.

The time point for reaching a sense of satisfaction or reduction of urgeto smoke or use tobacco after administration is individual, but may inexisting pharmaceutical forms for administering nicotine generally bereached after approximately 30 minutes when regarded as coinciding withtmax. According to the present invention, such a sense of satisfactionmay be reached after a shorter period of time due to a rapidtransmucosal uptake in the oral cavity due to the buffering and/or pHregulation and due to the absence of rate-limiting steps, such as tabletor lozenge melting, tablet or lozenge disintegration and dissolution andchewing gum mastication, followed by drug dissolution.

The Liquid Phase

The liquid phase of the present liquid pharmaceutical formulation maycomprise water. The liquid phase may also comprise an alcohol, such asethanol, glycerol, propylene glycol and polyethylene glycol, or mixturesthereof. It may also comprise one or more lipids. Further it maycomprise mixtures of the above ingredients. Other additives to theliquid pharmaceutical formulation

Other Additives may be Added Optionally to the Liquid PharmaceuticalFormulation.

Optional additives comprise one or more stabilizing additives, such asthose selected from the group consisting of antioxidants includingvitamin E, i.e., tocopheroles, vitamin C, i.e., ascorbic acid and itssalts, sodium pyrosulfite, butylhydroxytoluene, butylatedhydroxyanisole; and preservatives including parabenes, benzalkoniumchloride, chlorbutanol, benzyl alcohol, beta-phenylethylal alcohol,cetylpyridinium chloride; and chelating agents, such as EDTA; andgalates, such as propyl galate.

Further optional additives comprise one or more additives selected fromthe group consisting of:

enhancers, such as azone;

vitamins, such as vitamins C and E;

minerals, such as fluorides, especially sodium fluoride, sodiummonofluoro phosphate and stannous fluoride;

anti-odours, such as zinc and cyclodextrins;

propellants, such as 1,1,2,2-tetrafluoroethane (HFC-134a), optionallybeing liquefied, and 1,1,1,2,3,3,3-heptafluororpropane (HFC-227),optionally being liquefied;

sweeteners including one or more synthetic sweetening agents and/ornatural sugars, such as those selected from the groups consisting ofartificial sweeteners e.g., saccharin and its sodium and calcium salts,aspartame, acesulfame and its potassium salt, thaumatin andglycyrrhizin;

polyhydric alcohols such as sorbitol, xylitol, mannitol and glycerol;

monosaccharides including glucose (also called dextrose), fructose (alsocalled laevulose) and galactose;

disaccharides including saccharose (also called sucrose), lactose (alsocalled milk sugar) and maltose (also called malt sugar);

mixtures of sugars including liquid glucose syrup e.g., starchhydrolysates containing a mixture of chiefly dextrose, maltose, dextrinsand water, invert sugar syrup e.g., sucrose inverted by invertasecontaining a mixture of dextrose, laevulose and water, high sugarcontent syrups such as treacle, honey and malt extract; and mixturesthereof,

flavoring and/or aromatizing agents, such as those selected from the

group consisting of essential oils obtained by distillations, solventextractions or cold expressions of fresh or dried flowers, buds, leaves,stems, fruit, seeds, peel, bark, or root e.g., oil of peppermint,spearmint, eucalyptus, wintergreen, niaouli, clove, cardamom, cinnamon,bitter almond, coriander, caraway, ginger, juniper, orange, bitterorange, lemon, grapefruit, mandarine, bergamot, thyme, fennel androsemary;

natural flavors and aroma agents including either diluted solutions ofessential oils or concentrates of flavor components with natural originfrom e.g., fruits, berries, nuts, spices, mints, tobacco, cocoa, coffee,tea, vanilla, liquorice, caramel, toffee, honey, wine, liquors andbrews;

synthetic flavors and aroma agents consisting of mixtures of chemicalscomprising hydrocarbons, alcohols, aldehydes, esters, ketones, ethersand oxides blended to match the natural flavor of e.g., fruits, berries,nuts, spices, mints, tobacco, cocoa, coffee, tea, vanilla, liquorice,caramel, toffee, honey, wine, liquors or brews;

and mixtures thereof.

Surface Active Agents

One or more of the compounds of the liquid pharmaceutical formulationmay be solubilized in one or more surface active agents and/oremulsifiers, such as nonionic, cationic, anionic or zwitterionicsurfactants, including amphiphilic block copolymers, or mixturesthereof.

Specifically one or more of the compounds of the liquid pharmaceuticalformulation may be solubilized in one or more surface-active agentsselected from

nonionic surface-active agents including poloxamers, e g:poly(oxypropylene)-poly (oxyethylene) block copolymers, polyoxyethylenealkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylenesorbitan fatty acid esters, mono- and diglycerides and esters thereof,polyoxyethylene stearates, polyglycerolesters of fatty acids (includingpolyglycerolpolyricinoleic acid (PGPR)), and sorbitan fatty acid esters,

cationic surface-active agents including secondary, quaternary andtertianary ammonium compounds and cationic phospholipids,

anionic surface-active agents including fatty acid salts, lactylates,especially sodium and/or calcium stearoyllactylate, alkyl sulphates,alkyl sulphonates, latanol, and anionic phospholipids, such asphosphatidylserine,

zwitterionic surface-active agents including zwitterionic phospholipids,such as phosphatidylcholine and phosphatidylethanolamine,

or mixtures thereof,

preferably surface-active agents or mixtures thereof being nonionic.

Method for Delivering Nicotine in any Form to a Subject

According to the invention, a method for delivering nicotine in any formto a subject comprises the steps of:

a) administering to a subject a liquid pharmaceutical formulationproduct containing nicotine in any form according to the invention intothe oral cavity of the subject, and

b) allowing the nicotine in any form in the liquid pharmaceuticalformulation to be mixed with the saliva in the oral cavity and absorbedinto the blood plasma of the subject essentially by buccal uptake.

One embodiment results in a t_(max) of nicotine in venous blood of thesubject after about 3-30 minutes.

One further embodiment results in a t_(max) of nicotine in venous bloodof the subject after about 3-20 minutes.

In still one further embodiment, said nicotine in any form is absorbedresulting in a t_(max) of nicotine in venous blood of the subject afterabout 3-15 minutes.

Method for Obtaining Reduction of the Urge to Smoke or Use Tobacco

A method for obtaining reduction of the urge to smoke or usetobacco-containing material and/or for providing a sense of smokingsatisfaction without smoking according to the invention comprises thesteps of:

a) replacing at least partly the tobacco containing material with aliquid pharmaceutical formulation according to any of claims 1-22,

b) administering to a subject a liquid pharmaceutical formulationcontaining nicotine in any form according to any of claims 1-22 into theoral cavity of the subject, and

c) allowing the nicotine in any form in the liquid pharmaceuticalformulation to be absorbed by the subject essentially by buccal uptake.

The administration to the oral cavity takes place by spraying, droppingor pipetting, preferably by spraying, most preferably by spraying underthe tongue. The administration is intended for the oral cavity, not fore.g., the lungs or the upper respiratory tract.

In one embodiment said nicotine in any form results in a t_(max) ofnicotine in venous blood of the subject after about 3-30 minutes.

In one further embodiment said nicotine in any form results in a t_(max)of nicotine in venous blood of the subject after about 3-20 minutes.

In still one further embodiment said nicotine in any form results in at_(max) of nicotine in venous blood of the subject after about 3-15minutes.

Even further embodiments of the method for delivering nicotine to asubject may comprise the steps of combining at least one other methodfor obtaining reduction of the urge to smoke or use of tobacco.

The liquid pharmaceutical formulation may be used for obtaining a quickand/or sustained and/or complete reduction of the urge to smoke or usetobacco and/or for providing a sense of smoking satisfaction withoutsmoking as further discussed below.

The fast relief provides the subject with a sense of rapid smokingsatisfaction without smoking.

One embodiment reduces the urge to smoke or use of tobacco by reaching at_(max) of nicotine in venous blood of the subject after about 3-30minutes by the use of a liquid pharmaceutical formulation according tothe invention.

One further embodiment reduces the urge to smoke or use tobacco byreaching a t_(max) of nicotine in venous blood of the subject afterabout 3-20 minutes by the use of a liquid pharmaceutical formulationaccording to the invention.

Still one further embodiment reduces the urge to smoke or use tobacco byreaching a t_(max) of nicotine in venous blood of the subject afterabout 3-15 minutes by the use of a liquid pharmaceutical formulationaccording to the invention.

Cessation of the Urge to Smoke or Use Tobacco

For some of the users, it may be a goal to terminate the usage ofnicotine completely, due to several reasons e.g., health, economical,social or behavioral. This may be achieved by further decreasing thedelivered amount of nicotine in any form gradually over time. Inspecific embodiments of the invention, the method described above forobtaining craving relief may further comprise the steps of decreasingthe amount of nicotine in the liquid pharmaceutical formulationgradually over time, and/or the steps of reducing the incidence ofadministration of the liquid pharmaceutical formulation gradually overtime, and/or the steps of reducing the dosage size of the liquidpharmaceutical formulation gradually over time, so as to achieve arelief of tobacco craving and/or to achieve a sense of smokingsatisfaction. This method results in a weaning process gradually overtime.

Different types of smokers reach the sense of reduced craving atdifferent plasma levels of nicotine. This may, of course, affect theindividual types of programs for administering a liquid pharmaceuticalformulation according to the invention. Different types of smokersinclude e.g., peak seekers or smokers that crave for a plasma level ofnicotine constantly being above the level below which withdrawalsymptoms occur.

One strategy may be to lower the frequency of administering the liquidpharmaceutical formulation. Other embodiments include varying the doseof the nicotine in said liquid pharmaceutical formulation as well as thecombination of these two embodiments.

Systems for Delivering Nicotine and for Obtaining Craving Relief

According to the invention there is a system for delivering nicotine inany form to a subject. Such a system comprises a liquid pharmaceuticalformulation according to the invention and at least one other means forobtaining reduction of the urge to smoke.

Another system according to the invention may be a system for obtainingreduction of the urge to smoke or use tobacco and/or for providing asense of smoking satisfaction without smoking. Such a system comprises aliquid pharmaceutical formulation according to the invention and atleast one other method for obtaining reduction of the urge to smoke oruse tobacco. Other methods may be a concomitant or concurrent methodselected from the group consisting of administration through chewinggums, nasal sprays, transdermal patches, inhaling devices, lozenges,tablets and parenteral methods, subcutaneous methods, intravenousmethods, rectal methods, vaginal methods and transmucosal methods; oruse of tobacco.

In a specific embodiment, the at least one other method comprisesadministration of nicotine.

Use of the Liquid Pharmaceutical Formulation

The use of the liquid pharmaceutical formulation according to theinvention is for obtaining a fast and/or complete reduction of the urgeto smoke and use tobacco or for providing a sense of smoking withoutsmoking as described above.

The dose of the nicotine is chosen to give the subject an individualsensory perception and satisfaction with an effect of the nicotine inany form. The use of the liquid pharmaceutical formulation may also be asole use according to the invention or a combination with other means ormethods known in the field of drug abuse. Specifically, the presentinvention may be used in combination with other means as described abovein the methods in the paragraphs above.

The use may give a quick reduction of the urge to smoke or use tobaccowhereby is reached a t_(max) of nicotine in venous blood after about3-20 minutes.

In a specific embodiment, the use of the liquid pharmaceuticalformulation according to the invention will reduce the urge to smoke oruse tobacco by reaching a t_(max) of nicotine in venous blood of thesubject after about 3-15 minutes.

According to the invention, a use of a liquid pharmaceutical formulationaccording to the invention is for delivering nicotine in any form to asubject.

In one embodiment, the delivering of nicotine in any form results in at_(max) of nicotine in venous blood of the subject after about 3-30minutes.

In another embodiment, the delivering of nicotine in any form results ina t_(max) of nicotine in venous blood of the subject after about 3-20minutes.

In still another embodiment, the delivering of nicotine in any formresults in a t_(max) of nicotine in venous blood of the subject afterabout 3-15 minutes.

As readily shown and concluded from the figures, e.g., FIG. 4, theshorter the t_(max) the faster the relief of the craving, i.e., of theurge to smoke.

All publications, patents, and patent applications cited herein arehereby incorporated by reference in their entirety for all purposes. Theexamples set forth below are non-limiting and for illustrating thepresent invention. Alternatives and variations of the below exampleswithin the scope of the present invention as per the below claims may becarried out by a person skilled in the art. Ingredients as per the belowexamples may be exchanged for equivalent ingredients, preferably as perabove. The formulations according to Examples 2 and 3 were made forcomparative purposes as seen from FIG. 2.

EXAMPLE 1

Manufacturing of a 1000 ml formulation with 10 mg nicotine/ml and aroundpH 8.5.

Mixture 1

To a beaker containing 800 ml water of 90° C. was added 0.7 g methylpara-hydroxybenzoate, acting as preservative, and 0.3 g propylpara-hydroxybenzoate, acting as preservative. The additives weredissolved during stirring for about 10 minutes. Then was added 10.45 gsodium dihydrogen phosphate, acting as buffering agent, and 0.5 g EDTA,acting as chelating agent, to the solution, which was stirred for about5 minutes. Then the solution was cooled to 30° C. during stirring.

Mixture 2

To a beaker containing 15.9 g ethanol of room temperature, acting assolvent, was added 0.045 g peppermint oil, acting as flavoring agent.The liquid was mixed for 2 minutes.

Final Mixture

Mixture 2 was added during stirring to a beaker containing 150 ml water.Gently 10 g nicotine (base) was added to the beaker. Then Mixture 1 wasadded to the beaker and stirred for 5 minutes. The pH of the Finalmixture was checked and adjusted to about pH 8.5 with sodium hydroxide(20%) and to volume with water.

EXAMPLE 2

Manufacturing of a 1000 ml formulation with 10 mg nicotine/ml and aroundpH 7.0.

This Example 2 differs from Example 1 only for pH. The formulationaccording to Example 2 contains a non-alkalizing buffering agent. Thisformulation was for use as a comparison in FIG. 2.

Mixture 1

To a beaker containing 800 ml water of 90° C. was added 0.7 g methylpara-hydroxybenzoate, acting as preservative, and 0.3 g propylpara-hydroxybenzoate, acting as preservative. The additives weredissolved during stirring for about 10 minutes. Then was added 10.45 gsodium dihydrogen phosphate, acting as buffering agent, and 0.5 g EDTA,acting as chelating agent, to the solution, which was stirred for about5 minutes. Then the solution was cooled to 30° C. during stirring.

Mixture 2

To a beaker containing 15.9 g ethanol of room temperature, acting assolvent, was added 0.045 g peppermint oil, acting as flavoring agent.The liquid was mixed for 2 minutes.

Final Mixture

Mixture 2 was added during stirring to a beaker containing 150 ml water.Gently 10 g nicotine (base) was added to the beaker. Then Mixture 1 wasadded to the beaker and stirred for 5 minutes. The pH of the Finalmixture was checked and adjusted to about pH 7.0 with hydrochloric acidand to volume with water.

EXAMPLE 3

Manufacturing of a 1000 ml formulation with 10 mg nicotine/ml and aroundpH 6.0.

This Example 3 differs from Example 1 only for pH. The formulationaccording to Example 3 contains a non-alkalizing buffering agent. Thisformulation was for use as a comparison in FIG. 2.

Mixture 1

To a beaker containing 800 ml water of 90° C. was added 0.7 g methylpara-hydroxybenzoate, acting as preservative, and 0.3 g propylpara-hydroxybenzoate, acting as preservative. The additives weredissolved during stirring for about 10 minutes. Then was added 10.45 gsodium dihydrogen phosphate, acting as buffering agent, and 0.5 g EDTA,acting as chelating agent, to the solution, which was stirred for about5 minutes. Then the solution was cooled to 30° C. during stirring.

Mixture 2

To a beaker containing 15.9 g ethanol of room temperature, acting assolvent, was added 0.045 g peppermint oil, acting as flavoring agent.The liquid was mixed for 2 minutes.

Final Mixture

Mixture 2 was added during stirring to a beaker containing 150 ml water.Gently 10 g nicotine (base) was added to the beaker. Then Mixture 1 wasadded to the beaker and stirred for 5 minutes. The pH of the Finalmixture was checked and adjusted to about pH 6.0 with hydrochloric acidand to volume with water.

EXAMPLE 4

Manufacturing of a 1000 ml formulation with 17.5 mg nicotine/ml andaround pH 9.0.

Mixture 1

To a beaker containing 600 ml water of room temperature was added 12.0 gSynperonic® PE/F27, being a poloxamer acting as non-ionic surface activeagent. The additive was dissolved during stirring for about 20 minutes.Then was added 0.5 g EDTA, acting as chelating agent, and 0.4 g sodiumsaccharin, acting as sweetener, to the liquid which was stirred untilall ingredients were dissolved. Then was added 16.8 g sodium hydrogencarbonate, acting as buffering agent, and the solution was stirred untila clear solution was obtained.

Mixture 2

To a beaker containing 250.0 g ethanol of room temperature, acting assolvent, was added 0.7 g methyl para-hydroxybenzoate acting aspreservative, and 0.3 g propyl para-hydroxybenzoate acting aspreservative. The liquid was mixed until the ingredients were dissolved.Then was added 5.0 g peppermint oil, acting as flavoring agent, and 1.5g aroma agent. The liquid was mixed until a clear solution was obtained.

Final Mixture

Mixture 2 was gently added to Mixture 1 during stirring for about 1minute. Then was added 17.5 g nicotine (base) and the liquid was stirredfor about 2 minutes. The pH of the Final mixture was checked andadjusted to around pH 9.0 with hydrochloric acid. The Final mixture wastransferred to a 1000 ml volumetric flask and adjusted to 1000 ml volumeby water. Finally the pH of the solution was checked to remain at aroundpH 9.0.

EXAMPLE 5

Manufacturing of a 1000 ml formulation with 14.3 mg nicotine/ml andaround pH 9.0.

Mixture 1

To a beaker containing 600 ml water of room temperature was added 20.0 gSynperonic® PE/F27 being a poloxamer, acting as non-ionic surface activeagent. The additive was dissolved during stirring for about 20 minutes.Then was added 2.0 g Acesulfame K, acting as sweetener, to the liquidwhich was stirred until all ingredients were dissolved. Then was added20.0 g sodium hydrogen carbonate, acting as buffering agent, and theliquid was stirred until a clear solution was obtained.

Mixture 2

To a beaker containing 95.0 g ethanol of room temperature, acting assolvent, was added 3.5 g peppermint oil, acting as flavoring agent, and1.0 g aroma agent. The liquid was mixed until a clear solution wasobtained.

Final Mixture

Mixture 2 was gently added to Mixture 1 during stirring for about 1minute. Then was added 14.3 g nicotine (base) and the liquid was stirredfor about 2 minutes. The pH of the Final mixture was checked andadjusted to around pH 9.0 with hydrochloric acid. The Final mixture wastransferred to a 1000 ml volumetric flask and adjusted to 1000 ml volumeby water. Finally the pH of the solution was checked to remain at aroundpH 9.0.

The formulation according to Example 5 is a preferred composition.

EXAMPLE 6

Manufacturing of a 1000 ml formulation with 14.3 mg nicotine/ml andaround pH 9.0.

Mixture 1

To a beaker containing 600 ml water of room temperature was added 20.0 gSynperonic® PE/F27 being a poloxamer, acting as non-ionic surface activeagent. The additive was dissolved during stirring for about 20 minutes.Then was added 0.2 g benzalkonium chloride, acting as preservative, and2.0 g Acesulfame K, acting as sweetener, to the liquid which was stirreduntil all ingredients were dissolved. Then was added 20.0 g sodiumhydrogen carbonate, acting as buffering agent, and the liquid wasstirred until a clear solution was obtained.

Mixture 2

To a beaker containing 95.0 g ethanol of room temperature, acting assolvent, was added 3.5 g peppermint oil, acting as flavoring agent, and1.0 g aroma agent. The liquid was mixed until a clear solution wasobtained.

Final Mixture

Mixture 2 was gently added to Mixture 1 during stirring for about 1minute. Then was added 14.3 g nicotine (base) and the liquid was stirredfor about 2 minutes. The pH of the Final mixture was checked andadjusted to around pH 9.0 with hydrochloric acid. The Final mixture wastransferred to a 1000 ml volumetric flask and adjusted to 1000 ml volumeby water. Finally the pH of the solution was checked to remain at aroundpH 9.0.

The formulation according to Example 6 is a another preferredcomposition.

EXAMPLE 7

Manufacturing of a 1000 ml formulation with 14.3 mg nicotine/ml andaround pH 9.0.

Mixture 1

To a beaker containing 600 ml water of room temperature was added 20.0 gSynperonic® PE/F27 being a poloxamer, acting as non-ionic surface activeagent. The additive was dissolved during stirring for about 20 minutes.Then was added 0.5 g EDTA, acting as chelating agent, and 2.0 gAcesulfame K, acting as sweetener, to the liquid which was stirred untilall ingredients were dissolved. Then was added 20.0 g sodium hydrogencarbonate, acting as buffering agent, and the liquid was stirred until aclear solution was obtained.

Mixture 2

To a beaker containing 95.0 g ethanol of room temperature, acting assolvent, was added 0.7 g methyl para-hydroxybenzoate acting aspreservative, and 0.3 g propyl para-hydroxybenzoate acting aspreservative. The liquid was mixed until the ingredients were dissolved.Then was added 3.5 g peppermint oil, acting as flavoring agent, and 1.0g aroma agent. The liquid was mixed until a clear solution was obtained.

Final Mixture

Mixture 2 was gently added to Mixture 1 during stirring for about 1minute.

Then was added about 2 ml sodium hydroxide (50%) and 4 g nicotinebitartrate. The pH of the Final mixture was not allowed to decreasebelow pH 8 during the addition of the nicotine bitartrate. The precedingprocedure with adding of sodium hydroxide and nicotine bitartrate wasrepeated until totally 40.7 g nicotine bitartrate was added. The pH ofthe Final mixture was adjusted to around pH 9.0. The Final mixture wastransferred to a 1000 ml volumetric flask and adjusted to 1000 ml volumeby addition of water. Finally the pH of the solution was checked toremain at around pH 9.0.

EXAMPLE 8

Manufacturing of a 1000 ml formulation with 17.5 mg nicotine/ml and pH10.94.

To a beaker containing 950 ml water of room temperature was added 17.5 gnicotine (base) during stirring for about 5 minutes. The volume wasadjusted to 1000 ml volume by addition of water. Finally the pH waschecked.

EXAMPLE 9

Manufacturing of a 1000 ml formulation with 17.5 mg nicotine/ml and pH11.55.

To a beaker containing 950 ml water of room temperature was added 35 gsodium carbonate anhydrous during stirring until complete dissolution.Then 17.5 g nicotine (base) was added during stirring for about 5minutes. The volume was adjusted to 1000 ml volume by addition of water.Finally the pH was checked.

EXAMPLE 10

Manufacturing of a 1000 ml formulation with 15.65 mg nicotine/ml and pH11.79.

To a beaker containing 950 ml water of room temperature was added 158 gglycine sodium salt during stirring until complete dissolution. Then15.65 g nicotine (base) was added during stirring for about 5 minutes.The volume was adjusted to 1000 ml volume by addition of water. Finallythe pH was checked.

EXAMPLE 11

Buffer Capacity Determinations

Method: 10.0 ml of the respective below solutions was titrated with 0.1M HCl to pH 7.0. The amount of 0.1 M HCl needed to decrease pH from 9.0to 8.0 was determined.

Definitions: (1) Sodium hydrogen carbonate (NaHCO3). Mw: 84.0

(2) Disodium phosphate dodecahydrate (Na2HPO4, 12H2O) Mw: 358.1Ingredient\Batch DKN0293 DKN0294 DKN0295 DKN0296 DKN0290 DKN0291Nicotine (mg/ml) 10.0 10.0 10.0 NaHCO₃ (mg/ml) 16.8 16.8 8.4Na₂HPO₄,12H₂O 71.6 35.8 71.6 (mg/ml) Purified water ad 1 ml 1 ml 1 ml 1ml 1 ml 1 ml Buffer Capacity 26.5 9.5 50 15.8 40 29 PH = 9.0-8.0(mekv/l)All solutions were adjusted to a pH of 9.0 when needed. A higher pH maycause irritation and corrosion, which might be harmful to the tissue ofthe oral cavity.16.8 mg/ml of NaHCO3 corresponds to 0.2 M.71.6 mg/ml of Na2HPO4, 12H2O corresponds to 0.2 M.8.4 mg/ml of NaHCO3 corresponds to 0.1 M.35.8 mg/ml of Na2HPO4, 12H2O corresponds to 0.1 M

Nicotine base has an alkalizing effect, but has too weak a bufferingcapacity on its own. The buffering capacity of the formulation issignificantly and sufficiently increased when a buffering agent isadded.

The above data clearly show that the present formulations have a goodbuffering capacity, providing for the desired rapid transmucousal uptakeof nicotine.

A liquid pharmaceutical formulation according to the present inventionmay be administered using suitable devices being available on themarket, e.g., spray devices.

Analysis of Nicotine

The analysis of nicotine uptake and of the effect of the invention maybe done according to standard procedures known in the art, e.g., using abioanalysis for the determination of nicotine in the plasma of asubject.

Effects of the Invention

Comparative tests were conducted as described above under Legend offigures.

FIG. 1 shows that with a liquid pharmaceutical formulation according tothe present invention the venous blood plasma level of nicotine ascendssignificantly more rapidly than with Nicorette Microtab®. NicoretteMicrotab® has the same pharmacokinetic profile as, i.e., ispharmacologically equivalent with, Nicorette Gum® and all other nicotinechewing gums currently on the market. Nicotine chewing gums presentlyrepresent around half of the world sales of medicinalnicotine-containing products for smoking cessation and similarindications.

FIG. 2 shows that the higher the pH of a liquid pharmaceuticalformulation according to the present invention the faster the absorptionkinetics and the higher the plasma concentration of nicotine.

FIGS. 3 and 4 further show that a formulation according to the presentinvention provides for a fast craving relief manifested through asignificantly faster reduction in the urge to smoke compared to knownoral nicotine formulations.

Use for Therapy Treatment and Manufacturing

The liquid pharmaceutical formulation product according to the inventionmay be used in therapy. Said therapy may be a treatment of a disease ormedical indication selected from the group consisting of reduction inuse of tobacco, cessation of use of tobacco, other use of tobacco,temporary abstinence from abstaining from use of tobacco, Alzheimer'sdisease, Crohn's disease, Parkinson's disease, Tourette's syndrome, andulcerative colitis; and weight control.

Nicotine in any form may be used for the manufacturing of a liquidpharmaceutical formulation according to the invention for the treatmentof a disease or medical indication selected from the group consisting ofreduction in use of tobacco, cessation of use of tobacco, other use oftobacco, temporary abstinence from abstaining from using tobacco,Alzheimer's disease, Crohn's disease, Parkinson's disease, Tourette'ssyndrome, and ulcerative colitis; and weight control.

1. A method for delivering nicotine to a subject, the method comprisingthe steps of: (a) administering a liquid pharmaceutical compositioncomprising nicotine into the oral cavity of a subject by spraying,dropping or pipetting thereby providing oral transmucosal delivery ofnicotine to the subject without chewing or sucking, said compositionhaving an alkaline pH and further comprising one or more buffers in anamount sufficient to transiently increase the pH of liquid in the oralcavity of said subject by about 0.3 to about 4 pH units; and (b)allowing the nicotine to be systematically absorbed by buccal uptake. 2.The method of claim 1, wherein absorption of said nicotine results in at_(max) of nicotine in venous blood of the subject after about 3 to 30minutes.
 3. The method of claim 1, wherein absorption of said nicotineresults in a t_(max) of nicotine in venous blood of the subject afterabout 3 to 20 minutes.
 4. The method of claim 1, wherein absorption ofsaid nicotine results in a t_(max) of nicotine in venous blood of thesubject after about 3 to 15 minutes.
 5. The method of claim 1, whereinadministration of said composition is by spraying under the tongue. 6.The method of claim 1, wherein said composition, followingadministration to a subject, transiently increases the pH of the liquidof the oral cavity by about 0.5 to about 2.5 pH units.
 7. The method ofclaim 1, wherein said one or more buffers is a carbonate of an alkalimetal or of ammonium, a glycinate of an alkali metal or of ammonium, aphosphate of an alkali metal or of ammonium, a glycerophosphate of analkali metal or of ammonium, an acetate of an alkali metal or ofammonium, a gluconate of an alkali metal or of ammonium, or a citrate ofan alkali metal or of ammonium, or mixtures thereof.
 8. The method ofclaim 1, wherein the amount of nicotine administered to the oral cavityat each incidence of administration is about 0.05 to about 10 mgcalculated as the free base form of nicotine.
 9. A method for obtainingreduction of the urge to use tobacco containing material in a subject,the method comprising the steps of: (a) replacing some or all of thetobacco containing material with a liquid pharmaceutical compositioncomprising nicotine, said composition having an alkaline pH and furthercomprising one or more buffers in an amount sufficient to transientlyincrease the pH of liquid in the oral cavity of said subject by about0.3 to about 4 pH units; (b) administering the liquid pharmaceuticalcomposition into the oral cavity of a subject by spraying, dropping orpipetting thereby providing oral transmucosal delivery of nicotine tosaid subject without chewing or sucking; and (c) allowing the nicotineto be systematically absorbed by the subject.
 10. The method of claim 9,wherein the method reduces the urge to smoke.
 11. The method of claim10, wherein the method provides a sense of smoking satisfaction withoutsmoking.
 12. The method of claim 9, wherein absorption of said nicotineresults in a t_(max) of nicotine in venous blood of the subject afterabout 3 to 30 minutes.
 13. The method of claim 9, wherein absorption ofsaid nicotine results in a t_(max) of nicotine in venous blood of thesubject after about 3 to 20 minutes.
 14. The method of claim 9, whereinabsorption of said nicotine results in a t_(max) of nicotine in venousblood of the subject after about 3 to 15 minutes.
 15. The method ofclaim 9, wherein administration of said composition is by spraying underthe tongue.
 16. The method of claim 9, wherein said composition,following administration to a subject, transiently increases the pH ofthe liquid of the oral cavity by about 0.5 to about 2.5 pH units. 17.The method of claim 9, wherein said one or more buffers is a carbonateof an alkali metal or of ammonium, a glycinate of an alkali metal or ofammonium, a phosphate of an alkali metal or of ammonium, aglycerophosphate of an alkali metal or of ammonium, an acetate of analkali metal or of ammonium, a gluconate of an alkali metal or ofammonium, or a citrate of an alkali metal or of ammonium, or mixturesthereof.
 18. The method of claim 9, wherein the method for obtainingreduction of the urge to use tobacco containing material is performed incombination with one or more additional methods for obtaining reductionof the urge to use tobacco containing material.
 19. The method of claim18, wherein the method for obtaining reduction of the urge to usetobacco containing material is performed in combination with theadministration of nicotine through chewing gums, nasal sprays,transdermal patches, inhaling devices, lozenges, tablets, parenteralmeans or methods, subcutaneous means, intravenous means, rectal means,vaginal means or transmucosal means.
 20. A method for treating adisease, the method comprising the steps of: (a) administering a liquidpharmaceutical composition comprising nicotine into the oral cavity of asubject by spraying, dropping or pipetting thereby providing oraltransmucosal delivery of nicotine to the subject without chewing orsucking, said composition having an alkaline pH and further comprisingone or more buffers in an amount sufficient to transiently increase thepH of liquid in the oral cavity of said subject by about 0.3 to about 4pH units; and (b) allowing the nicotine to be systematically absorbed bybuccal uptake, wherein the disease is selected from the group consistingof addiction to tobacco or nicotine, Alzheimer's disease, Crohn'sdisease, Parkinson's disease, Tourette's syndrome, ulcerative colitis,and weight control.